I plan a career as an independent investigator at an academic institution where I will hold clinical and teaching responsibilities. My research experience to date has involved the study of the biology of antigen presentation in human B cells and the role of complement receptors in this process. I intend to focus my future research on the analysis of the genetic and environmental factors which lead to the development of autoimmune disease. In the project described in this proposal, I will study B cell signaling in a murine model for systemic lupus erythematosus in an effort to identify candidate genes which are associated with disease. My career development will be enhanced by the many educational opportunities available at the University of Colorado Health Sciences Center, National Jewish Center and the Barbara Davis Center, including weekly seminars and journal clubs, laboratory meetings with Drs. Michael Holers, John Cambier, and Brian Kotzin, and formal coursework in Immunology, Biochemistry and Molecular Biology. The research project described in this proposal was developed from the observation that resting splenic B cells from autoimmune-prone New Zealand Black (NZB) mice demonstrate a pronounced defect in apoptosis induction after surface IgM (sIgM) ligation. These cells were found to exhibit a specific signal transduction alteration involving CD19. This abnormality, in addition to currently uncharacterized defects in other NZB signaling molecules, may be causally related to both the apoptosis defect as well as the autoimmune phenotype in NZB and (NZB X New Zealand White [NZW]) F1 mice. The goals of this project are to identify other potential disease-related NZB genes by testing for alterations in the signaling pathways mediated by sIgM and CD40, to characterize any structural defect in NZB CD19 and other abnormal genes which are identified, to determine the effect of the altered gene products on signaling, and to track the NZB alleles for disease association in congenic strains crossed with NZW. This strategy of identifying candidate NZB disease-associated genes based on alterations in B cell signaling pathways involved in the regulation of apoptosis is expected to provide important new insight into the pathogenesis of systemic lupus erythematosus.